Many tumors escape surveillance by our immune system. In cancer patients there is clearly a quantitative and/or qualitative defect in the immune system's specific mechanisms to delete tumor cells. One of these mechanisms is provided by the cytotoxic T cells (CTL) that can recognise and kill cells infected by virus or transformed into cancer cells. Previously it was postulated that dendritic cells (DC) stimulate T-helper cells which, in turn, provide help for the activation of CTL. The present inventors have demonstrated that the T-helper cell is not providing helper signals directly to the CTL (by secretion of IL2), but rather, the T-helper cell is providing a signal to the DC that induces yet uncharacterised cell surface and/or soluble molecules that can activate CTL in the absence of T-helper cells. The signal provided by the T-helper cell to the DC is mediated by CD40L-CD40 interaction. This novel finding has provided an unique opportunity for cancer immunotherapy.
The immune system is capable of killing autologous cells when they become infected by virus or when they transform into cancer cells. Such a potentially dangerous mechanism must, clearly, be under tight control. The immune system's CTL circulate as inactive precursors. To be activated, the precursor T-killer cell must recognise its specific antigen peptide, which is presented as MHC class I molecules on professional APC. However, in order to prime these T cells, the APC also need to present the antigen in a proper costimulatory context as provided by, amongst others, the costimulatory surface molecules B7.1 and B7.2 and by the lympokine IL-12.
Until recently it was believed that a T-helper cell that recognises the same antigen on the same APC is needed to fully activate the CTL. The specific T-helper cell would supply cytokines such as IL-2 needed for the activation of the CTL. Guerder and Matzinger (J. Exp. Med. 176:553 (1992)), however, proposed the “licensing” model for CTL activation. In this model it was suggested that the T-helper cell, when recognising its antigen on a professional APC, would deliver an activation signal to the APC that as a result would be able to subsequently activate a CTL without the need for the T-helper cell to be present. Only very recently, the molecular mechanism of the licensing model has been elucidated. Schoenberger et al. (Nature 393:480 (1998)), described the role of the CD40L-CD40 pathway in the licensing model. Interaction between T-helper cell and DC through the CD40-CD40L binding results in activation of the DC, thereby enabling the DC to efficiently prime naive CTL.
DC circulate through the tissues of our body and in this manner can collect, process and present antigens. After collection of antigens, they migrate to the draining lymph nodes where they present antigen to the T cells. It is well known that a DC needs to be activated to perform optimally. Resting DC express only modest levels of MHC and costimulatory molecules and are poor stimulators of T cells. DC can be activated by inflammatory cytokines and bacterial products, which results in upregulation of MHC and costimulatory molecules. Activation of DC into fully mature DC, expressing optimal levels of MHC molecules, costimulatory molecules and lymphokines such as IL-12, requires additional triggering of these cells through the CD40 receptor. Consequently, the combination of inflammatory cytokines at the site of antigen uptake and the CD40L-CD40 interaction during the T-helper cell interaction result in an optimal capacity to license the DC for CTL activation.
Many tumors escape immune surveillance by specific CTL mechanisms. If DC gather tumor antigens under non-inflammatory conditions the number of T-helper cells that are activated may be to low to induce enough CTL to be activated to induce an appropriate anti-tumor response. This concept has prompted investigators to help the immune system by administration of cytokines such as IL-2 and IL-12 that directly stimulate CTL activity or by boosting antigen presentation by administration of tumor cells transfected with GM-CSF. These strategies have met variable but encouraging results.
It is clear that there is still a great need to find ways to generate and/or enhance protective anti-tumor responses involving cellular and humoral immunity. The CD40 activation pathway was found to be a major immunoregulatory pathway for the generation of primary humoral and cellular immune responses. As described above, the CD40 pathway on DC is responsible for the induction of anti-tumor CTL responses. In addition, activation of the CD40 pathway on macrophages stimulates a strong tumoricidal activity.